This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Simian immunodeficiency virus (SIV) becomes more virulent upon in vivo evolution. Also, tissue specific variants have been identified that may impact infection and disease. The mechanisms by which SIV acquires increased potential to replicate, and thereby infect the host and drive disease progression, are not well understood. Whether mutations that evolve to enhance persistence and disease come at a cost to fitness is also unclear. Identifying the molecular determinants of fitness and virulence will provide a basis for uncovering the host-virus interactions important for efficient virus replication. The goal of the study is to identify the fitness and virulence determinants of early and late stage variants of SIV, and to define the host cell interactions important for supporting virus replication.